Developing clinical investigational drugs from probes/leads involves optimization of their drug-like propertieswhether for small molecules, biologics, or gene therapiesand understanding their pharmacokinetics and pharmacodynamics in relation to their desired mechanism-of-action, as well as their toxicological profiles. These novel entities must further be formulated for optimal bioavailability, and scalable Good Manufacturing Practices (GMP) developed. Together, such studies form the basis of an Investigational New Drug (IND) application, which the FDA must clear to allow clinical testing to proceed. The immediacy and scale of loss of life and health due to the opioid crisis requires a focus on the development of new clinically useable medications, and diversification of approaches to create them. The Therapeutic Development Branch (TDB) has a well-established record of innovation and productivity that is being directed to serve the needs of the opioid crisis. NCATS intramural scientific staff have extensive experience in developing diverse therapeutic modalities, ranging from small and large molecule compounds to biologics and gene therapies. These in-house brains and hands are complemented by pre-existing relationships with Contract Research Organizations (CROs) with strong track records of working with NCATS. NCATS scientists collaborate with external researchers across the preclinical development spectrum. TDB supports projects at earlier stages of development in need of significant optimization and comprehensive IND-enabling studies. TDB also supports more advanced projects - ready for a faster launch directly into IND-enabling studies - for more rapid progression towards clinical testing. Ongoing efforts include the development of important research tools and resources. Patient-derived cell-based assays will help identify and prioritize new molecular targets and candidate compounds for further optimization and development. Refined animal models of pain and addiction will help validate existing efficacy data for new drug candidates to allow key IND-enabling studies to begin.